malaria vaccines

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malaria vaccines:

malaria vaccines Dr.p.nalini Malaria

Introduction :

Introduction Malaria affects about 70-80 million people and leads to almost ,900,000 deaths annually (World Health Organization,). Caused by infection with protozoan parasite Plasmodium : P. falciparum , P. vivax , P. ovale , P. malariae , and P. knowlesi.P . falciparum and P. vivax cause most of the malarial infections worldwide. P. falciparum is associated with the most severe disease. The vast majority of malaria cases occur via infection from Anopheles mosquitoes in endemic regions. Infections acquired congenitally or via transfusions or contaminated needles are known to occur but are rare. Screening of blood donors has reduced the risk of transfusion-transmitted malaria.

FORMS OF AMTIMALARIAL THERAPY ::

FORMS OF AMTIMALARIAL THERAPY : CAUSAL PROPHYLAXIS : To elimnate the pre erythrocytic phase in liver. B. SUPPRESSIVE PROPHYLAXIS : To kill the erythrocytic phase & thus prevents the malrial fever. C. CLINICAL CURE : To treat the disease D. RADICAL CURE : Total eradication of the parasite. GAMETOCIDAL : To stop the disease transmission.

Classification:

Classification

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CLASS 1 – asexual erythrocytic blood schizonticides : Chloroquine , Mefloquine , Quinine,Pyrimethamine,Sulfadoxine . CLASS II – Primary hepatic & asexual RBC schizonticides : Atovaquone , Proguanil CLASS III – Primary hepatic schizonticides & merozoitocides , & gametocides : Primaquine

MALARIA CHEMOPROPHYLAXIS ::

MALARIA CHEMOPROPHYLAXIS : Limited to nonimmune travellers , endemic zones , pregnant mothers. Eryhtrocytic schozontocidal drugs are used. Chq- 300 mg wkly Proguanil -200 mg daily with Chq Mefloquine - 250 mg wky Doxycycline – 100 mg daily 4 wks

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The global burden of P. falciparum malaria is increasing due to drug-resistant parasites and insecticide-resistant mosquitoes; this is illustrated by re-emergence of the disease in areas that had been previously malaria-free. There has been a major scaling-up in distribution of malaria control measures particularly since the advent ofThe Global Fund to Fight AIDS, Tuberculosis and Malaria. Early evidence of resistance to artemisinins , the most important class of antimalarials , is now confirmed, having manifested as delayed parasite clearance times in the western region of Cambodia on the border with Thailand. The Bill andMelinda Gates Foundation has launched a call for the aim of the malaria community to shift from sustained control to eradication. It is agreed that eradication is not possible with current tools and that research and development of new drugs, diagnostics, insecticides and a cost-effective deployable vaccine will be needed to facilitate eradication.

Malaria vaccine community goal:

Malaria vaccine community goal Strategic Goal: To develop an 80% efficacious malaria vaccine by 2025 that would provide protection for at least four years Landmark goal: To develop and license a first-generation malaria vaccine that has protective efficacy of more than 50% against severe disease and death and lasts longer than one year

Steps in malaria vaccine development :

Steps in malaria vaccine development Research and preclinical development: Identify relevant antigens and create vaccine concept; preclinical evaluation; develop vaccine manufacturing process. Phase I clinical trials: Preliminary evaluation of the safety profile and immune response in malaria-naïve and malaria-exposed populations. Phase II clinical trials: Monitor safety and potential side effects; measure immune response; evaluate efficacy against infection and clinical disease; and determine optimum dosage and schedule. Phase III clinical trials: Continue to monitor safety and potential side effects, and evaluate efficacy on a large scale. Submission to regulatory authorities: Submit application to regulatory authorities for approval to market Introduction: Make vaccine available for use. Phase IV clinical trials: Conduct post-marketing safety monitoring; measure duration of protection and assess vaccine compliance.

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Vaccines are often the most cost-effective tools for public health.Yet no effective vaccine for malaria has so far been developed. Despite this, researchers remain hopeful for several reasons, A.the first of these being that individuals who are exposed to the parasite in endemic countries develop acquired immunity against disease and death. Such immunity does not however prevent malaria infection; immune individuals often harbor asymptomatic parasites in their blood. B.research shows that if immunoglobulin is taken from immune adults, purified and then given to individuals that have no protective immunity, some protection can be gained. In addition to this, clinical and animal studies have shown that experimental vaccination has some degree of success.

Challenges :

Challenges The diversity of the parasite: P. falciparum has demonstrated the capability, through the development of multiple drug-resistance parasites, of evolutionary change. Has a very high rate of replication, much higher than that actually needed to ensure transmission in the parasite’s life cycle. This enables pharmaceutical treatments that are effective at reducing the reproduction rate, but not halting it, to exert a high selection pressure, thus favoring the development of resistance. The process of evolutionary change is one of the key considerations necessary when considering potential vaccine candidates. The development of resistance could cause a significant reduction in efficacy of any potential vaccine thus rendering useless a carefully developed and effective treatment

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Choosing to address the symptom or the source There are two main types of immune response than could be elicited by the parasite. These are anti-parasitic immunity and anti-toxic immunity. "Anti-parasitic immunity" addresses the source; it consists of humoral immunityand a cell-mediated immune response. Ideally a vaccine would enable the development of anti- plasmodial antibodies in addition to generating an elevated cell-mediated response. Potential vaccines exert their effect by activating the complement cascade, stimulating endocytosis through adhesion to an external surface of the antigenic substances, thus ‘marking’ it as offensive.In the case of malaria both systems would be targeted to attempt to increase the potential response generated, thus ensuring the maximum chance of preventing disease.

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" Anti-toxic immunity" addresses the symptoms; it refers to the suppression of the immune response associated with the production of factors that either induce symptoms or reduce the effect that any toxic by- product,Eg : it has been shown that TNF- α has a central role in generating the symptoms experienced in severe P. falciparum malaria. Thus a therapeutic vaccine could target the production of TNF-a, preventing respiratory distress and cerebral symptoms. This approach has serious limitations as it would not reduce the parasitic load; rather it only reduces the associated pathology. As a result, there are substantial difficulties in evaluating efficacy in human trials. Taking this information into consideration an ideal vaccine candidate would attempt to generate a more substantial cell-mediated and antibody response on parasite presentation. This would have the benefit of increasing the rate of parasite clearance, thus reducing the experienced symptoms and providing a level of consistent future immunity against the parasite

Potential targets of a vaccine:

Potential targets of a vaccine By their very nature, protozoa are more complex organisms than bacteria and viruses, with more complicated structures and life cycles. This presents problems in vaccine development but also increases the number of potential targets for a vaccine. These have been summarised into the life cycle stage and the antibodies that could potentially elicit an immune response. The life cycle of the malaria parasite is particularly complex, presenting initial developmental problems. Despite the huge number of vaccines available at the current time, there are none that target parasitic infections. The distinct developmental stages involved in the life cycle present numerous opportunities for targeting antigens, thus potentially eliciting an immune response. Theoretically , each developmental stage could have a vaccine developed specifically to target the parasite. Moreover, any vaccine produced would ideally have the ability to be of therapeutic value as well as preventing further transmission and is likely to consist of a combination of antigens from different phases of the parasite’s development.

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"pre- erythrocytic " or "hepatic" phase- A vaccine at this stage must have the ability to protect against sporozoites invading and possibly inhibiting the development of parasites in the hepatocytes (through inducing cytotoxic T-lymphocytes that can destroy the infected liver cell.If any sporozoites evaded the immune system they would then have the potential to be symptomatic and cause the clinical disease.

erythrocytic phase:

erythrocytic phase A vaccine here could prevent merozoite multiplication or the invasion of RBC. This approach is complicated by the lack of MHC expression on the surface of erythrocytes. Instead, malarial antigens are expressed, and it is this towards which the antibodies could potentially be directed. Another approach would be to attempt to block the process of erythrocyte adherence to endothelium . It is thought that this process is accountable for much of the clinical syndrome associated with malarial infection; therefore a vaccine given during this stage would be therapeutic and hence administered during clinical episodes to prevent further deterioration.

sexual stage.:

sexual stage. This would not give any protective benefits to the individual inoculated but would prevent further transmission of the parasite by preventing the gametocytes from producing multiple sporozoites in the gut wall of the mosquito. It therefore would directed at eliminating the parasite from areas of low prevalence or to prevent the development and spread of vaccine-resistant parasites. This type of transmission-blocking vaccine is potentially very important. The evolution of resistance in the malaria parasite occurs very quickly, potentially making any vaccine redundant within a few generations. This approach to the prevention of spread is therefore essential. Another approach is to target the protein kinases which are present during the entire lifecyle of the malaria parasite. Research is underway on this, yet production of an actual vaccine targeting these protein kinases may still take a long time.

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P. falciparum reticulocyte -binding protein homologue 5 (PfRH5), PfEMP1, one of the proteins known as variant surface antigens (VSAs) produced by Plasmodium falciparum are other potential targets. Mix of antigenic components Increasing the potential immunity generated against Plasmodia can be achieved by attempting to target multiple phases in the life cycle. This is additionally beneficial in reducing the possibility of resistant parasites developing. The use of multiple-parasite antigens can therefore have a synergistic or additive effect. One of the most successful vaccine candidates currently in clinical trials consists of recombinant antigenic proteins to the circumsporozoite protein

Vaccine delivery system:

Vaccine delivery system The selection of an appropriate system is fundamental in all vaccine development, but especially so in the case of malaria. A vaccine targeting several antigens may require delivery to different areas and by different means in order to elicit an effective response. Some adjuvants can direct the vaccine to the specifically targeted cell type—e.g. the use of Hepatitis B virus in the RTS,S vaccine to target infected hepatocytes —but in other cases, particularly when using combined antigenic vaccines, this approach is very complex. Some methods that have been attempted include the use of two vaccines, one directing RBC and the other the hepatic stage . These two vaccines could then be injected into two different sites, thus enabling the use of a more specific and potentially efficacious delivery system.

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The epidemiology of malaria varies enormously across the globe, and has led to the belief that it may be necessary to adopt very different vaccine development strategies to target the different populations. A Type 1 vaccine is suggested for those exposed mostly to P.falciparum malaria in sub-Saharan Africa, with the primary objective to reduce the number of severe malaria cases and deaths in infants and children exposed to high transmission rates. The Type 2 vaccine could be thought of as a ‘ travellers’ vaccine’, aiming to prevent all cases of clinical symptoms in individuals with no previous exposure. Problems with the current available pharmaceutical therapies include costs, availability, adverse effects and contraindications, inconvenience and compliance many of which would be reduced or eliminated entirely if an effective (greater than 85-90%) vaccine was developed.

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The earliest vaccines attempted to use the parasitic circum sporozoite (CS) protein. This is the most dominant surface antigen of the initial pre- erythrocytic phase. The CSP was a vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporozoite protein, but additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9). However at an early stage a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia whilst the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed, this was also not observed. problems were encountered due to low efficacy,reactogenicity & low immunogenicity.

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The NYVAC-Pf7 multistage vaccine attempted to use different technology, incorporating seven P.falciparum antigenic genes. These came from a variety of stages during the life cycle. CSP and sporozoite surface protein 2 (called PfSSP2) were derived from the sporozoite phase. The liver stage antigen 1 (LSA1), three from the erythrocytic stage ( merozoite surface protein 1, serine repeat antigen and AMA-1) and one sexual stage antigen (the 25-kDa Pfs25) were included. This was first investigated using Rhesus monkeysand produced encouraging results: 4 out of the 7 antigens produced specific antibody responses (CSP, PfSSP2, MSP1 and PFs25). Later trials in humans, despite demonstrating cellular immune responses in over 90% of the subjects had very poor antibody responses. Despite this following administration of the vaccine some candidates had complete protection when challenged with P.falciparum . This result has warranted ongoing trials.

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A Totally Synthetic Polyoxime MalariaVaccine Containing Plasmodium falciparum B Cell and Universal T Cell Epitopes Responses in Volunteers of Diverse Elicits

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In 1995 a field trial involving [NANP] proved to be very successful. Out of 194 children vaccinated none developed symptomatic malaria in the 12 week follow up period and only 8 failed to have higher levels of antibody present. The vaccine consists of the schizont export protein and repeats of the sporozoite surface protein [NANP]. Limitations of the technology exist as it contains only 20% peptide and has low levels of immunogenicity. It also does not contain any immunodominant T-cell epitopes .

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RTS,S is the most recently developed recombinant vaccine. It consists of the P. falciparum circumsporozoite protein from the pre- erythrocytic stage. The CSP antigen causes the production of antibodies capable of preventing the invasion of hepatocytes and additionally elicits a cellular response enabling the destruction of infected hepatocytes . The CSP vaccine presented problems in trials due to its poor immunogenicity. The RTS,S attempted to avoid these by fusing the protein with a surface antigen from Hepatitis B, hence creating a more potent and immunogenic vaccine. When tested in trials an emulsion of oil in water and the added adjuvants of monophosphoryl A and QS21 (SBAS2), the vaccine gave 7 out of 8 volunteers challenged with P. falciparum protective immunity.

Vaccine development strategies for the future:

Vaccine development strategies for the future The development of a vaccine of therapeutic and protective benefit against the malaria parasite requires a novel approach as to date there are no vaccines available that effectively target a parasitic infection. The focus so far has been predominately on the use of sub-unit vaccines. The use of live, inactivated or attenuated whole parasites is not feasible and therefore antigenic particles, or subunits, from the parasite are isolated and tested for immunogenicity . The most recent advances in the field of sub-unit vaccine development include the use of DNA vaccination. This approach involves removing sections of DNA from the parasitic genome and inserting the sequences into a vector, examples including plasmid genomes, attenuated DNA viral genomes, liposomes or proteoliposes , and other carrier complex molecules.

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When inoculated the plasmid or attenuated virus is endocytosed into a host cell, the DNA sequence is then incorporated into the host DNA and replicated by protein synthesis. The proteins then produced are expressed on the cell surface membrane of the ‘infected’ cell. These bind to the HLA molecules, priming T cells and therefore creating a population of memory T cells specific to the inoculated DNA sub-unit. This technique has been shown to produce a high rate of T cell response but poor level of antibody production. The efficacy of DNA vaccines can be assessed using an ELISPOT assay. This approach of potentially allowing the modification of vaccine candidates to improve development techniques and further scientific understanding is known as ‘iterative development’. The advantage of DNA vaccines over classical attenuated vaccines are numerous and include being able to mimic MHC class 1 CD8+ T cell specific responses that potentially could reduce some of the safety concerns associated with vaccine therapy and additionally provide a substantial reduction in production cost and due to the nature of DNA vaccines, increased ease of storage.

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India opens malaria vaccine center 06 March 2012 at the Pune International Biotech Park on 30 January, officials from PATH's Malaria Vaccine Initiative (MVI), the Infectious Disease Research Institute (IDRI) and Gennova gathered to inaugurate a $7.9 million facility dedicated to manufacturing vaccines. Gennova will provide the expertise to support the facility's construction and operation. The IDRI brings its pipeline of adjuvants to the table. the first product to undergo testing at the new center will be a malaria vaccine that includes antigens specific to the parasite's sexual stage together with one of three adjuvants that have already been used in human trials in the US and Europe. "If any new adjuvant is found to be more promising," he says, "we will follow guidance from the Indian Department of Biotechnology and the Drugs Controller of India about how to test it in preclinical and clinical studies." Maharaj Kishan Bhan , secretary for the Indian Department of Biotechnology, applauds the effort. "We welcome this initiative between a private company and nonprofit partners, each with its own strengths," he said. Visiting

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Phase 3, randomized, controlled, double-blind trial is was conducted at 11 centers in 7 African countries. Done to evaluate vaccine efficacy, safety, and immunogenicity for 32 months after the first dose of study vaccine in children 6 to 12 weeks of age or 5 to 17 months of age at enrollment. The trial includes three study groups in each age category: infants who received three doses of RTS,S/AS01 administered at 1-month intervals and a booster dose 18 months after the third dose, infants who

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